丝裂霉素抑制PI3K-AKT-mTOR信号通路对前列腺癌小鼠原位细胞移植模型的作用与机制研究

目的 探究丝裂霉素干预治疗小鼠原位注射前列腺癌中的作用与机制.方法 50只C57BL/6小鼠随机分为对照组、假手术组、模型组和丝裂霉素高低给药组,RM-1细胞悬液于两侧前列腺侧叶造模,假手术组注入等体积的PBS溶液,对照组小鼠仅行开腹手术.高低给药组分别腹腔注射1、2 mg/kg的丝裂霉素PBS溶液,对照组、假手术组和...     

Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway: An emerging treatment strategy for squamous cell lung carcinoma

Squamous cell lung carcinoma accounts for approximately 30% of all non-small cell lung cancers (NSCLCs). Despite progress in the understanding of the biology of cancer, cytotoxic chemotherapy remains the standard of care for patients with squamous cell lung carcinoma, but the prognosis is generally poor. The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is one of the most commonly activated signaling pathways in cancer, leading to cell proliferation, survival, and differentiation. It has therefore become a major focus of clinical research. Various alterations in the PI3K/AKT/mTOR pathway have been identified in squamous cell lung carcinoma and a number of agents targeting these alterations are in clinical development for use as single agents and in combination with other targeted and conventional treatments. These include pan-PI3K inhibitors, isoform-specific PI3K inhibitors, AKT inhibitors, mTOR inhibitors, and dual PI3K/mTOR inhibitors. These agents have demonstrated antitumor activity in preclinical models of NSCLC and preliminary clinical evidence is also available for some agents. This review will discuss the role of the PI3K/AKT/mTOR pathway in cancer and how the discovery of genetic alterations in this pathway in patients with squamous cell lung carcinoma can inform the development of targeted therapies for this disease. An overview of ongoing clinical trials investigating PI3K/AKT/mTOR pathway inhibitors in squamous cell lung carcinoma will also be included.     

高血糖对原发性肝癌疗效及预后的影响

[目的]探讨高血糖对原发性肝癌疗效、预后的影响及在肝癌诊治中的临床意义。[方法]142例肝癌患者接受手术、介入放疗、生物治疗等单一及综合治疗。分析肝癌合并高血糖的疗效，及肝癌的多种预后因素与生存率的关系。[结果]正常血糖组与高血糖组在生存率等方面无显著差异。预后主要与临床分期、肝功能分级、合并并发症与否等有关。[结论]高血糖并不影响肝癌的预后，高血糖不能作为肝癌诊治中的一个不利因素。     

老年食管癌三维适形与调强放射治疗疗效比较

目的比较老年食管癌三维适形放射治疗(3D-CRT)或调强放疗(IMRT)的疗效及其预后相关因素。方法回顾性分析153例65岁以上老年食管癌患者的临床资料,105例行3D-CRT、48例行IMRT,采用SPSS11.5统计软件比较分析生存率及预后影响因素。结果放疗后食管造影评价CR 71例、PR 78例、NR 4例,总有效率(CR+PR)为97.4%;全组1、3年生存率和局部控制率分别为70.6%、34.2%和76.2%、51.1%。3D-CRT与IMRT组资料相比,IMRT组胸中下段及淋巴结转移者较多、CT食管肿瘤最大径较大、放疗剂量更高、联合化疗者更多(P<0.05);而性别、年龄、T分期、放疗前进食情况及食管造影长度两组间比较差异无统计学意义(P>0.05)。3D-CRT与IMRT组1、3年生存率和局部控制率比较,差异无统计学意义(P>0.05),分层分析中两组生存率比较,差异无统计学意义(P>0.05)。全组单因素分析显示,治疗前进食情况、病变部位、T分期、淋巴结转移与否、食管造影显示病变长度、CT肿瘤最大直径、化疗和近期疗效与预后生存有关(P<0.05);Cox多因素分析仅化疗和CT肿瘤最大直径为独立预后因素(P<0.05)。结论老年食管癌IMRT与3D-CRT比较无明显生存优势,联合化疗及肿瘤最大直径小者放疗疗效较好,但需进一步前瞻性研究。     

Early Access Program Results From Turkey and a Literature Review on Daratumumab Monotherapy Among Heavily Pretreated Patients With Relapsed/Refractory Myeloma

BackgroundIn countries where frontline drug approval is limited to first-generation proteasome inhibitors or immunomodulatory drugs, relapses have been both more frequent and less durable. We investigated real world data on the efficacy and safety of daratumumab monotherapy among patients with relapsed refractory multiple myeloma (RRMM) from Turkey using a prospective early access program.Patients and MethodsA total of 42 patients with RRMM after a minimum of 3 previous lines of proteasome inhibitor/immunomodulatory drug-based treatments were included from 25 centers across Turkey. Daratumumab monotherapy was administered intravenously at a dose of 16 mg/kg weekly (cycles 1-2), on alternate weeks (cycles 3-6), and monthly thereafter.ResultsThe median daratumumab monotherapy duration was 5.5 months (range, 0.2-28.7 months). The overall response rate was 45.2%, including 14 (33.3%) partial responses, 4 (9.5%) very good partial responses, and 1 (2.4%) complete response. The median duration of response was 4.9 months. The median progression-free survival (PFS) was 5.5 (95% confidence interval, 2.6-8.4 months) with 12- and 18-month PFS rates of 35.7% and 31.0%, respectively. The median overall survival was not reached; the 12- and 18-month overall survival rates were 64.3% and 59.5%, respectively. The depth of response had a significant effect on PFS (log-rank test, P = .026). Overall, of the 76 adverse events reported, 33 (43.4%) were grade ≥ 3; only 4 (9.52%) were grade 3 infusion-related reactions. No infusion-related reactions or adverse events led to treatment discontinuation.ConclusionThe present findings from our daratumumab early access program have confirmed the efficacy and safety profile of daratumumab monotherapy in heavily pretreated Turkish patients with RRMM.     

ACTH-Secreting Neuroendocrine Carcinoma of the Cecum: Case Report and Review of the Literature

Background

Approximately 30% of neuroendocrine tumors (NETs) present with secretory syndromes or develop one during the course of the disease. Cushing syndrome caused by a gastrointestinal tract NET is rare, with limited published information. We describe a patient with florid Cushing syndrome due to ectopic adrenocorticotropic hormone (ACTH) from a NET of colonic origin. A literature review was conducted to describe the spectrum of this clinical and pathologic entity as reported in the scientific literature.

MicroRNA-122 Promotes Proliferation,Invasion and Migration of Renal Cell Carcinoma Cells Through the PI3K/Akt Signaling Pathway

Objective: MicroRNAs (miRNAs) are a small class of non-coding, single-stranded RNAs with a criticalrole in genesis and maintenance of renal cancer mainly through binding to 3’-untranslated regions (3’UTR) oftarget mRNAs, which causes a block of translation and/or mRNA degradation. The aim of the present studywas to investigate the potential effects of miR-122 in human renal cell carcinomas. Methods: The expressionlevel of miR-122 was quantified by qRT-PCR. MTT, colony formation, invasion and migration assays were usedto explore the potential functions of miR-122 in human renal cell carcinoma cells. Results: Cellular growth,invasion and migration in two A498 and 786-O cells were significantly increased after miR-122 transfection.Further experiments demonstrated that overexpression of miR-122 resulted in the increase of phospho-Akt(Ser473) and phospho-mTOR (Ser2448), then activation of mTOR targets, p70S6K and 4E-BP1. Conclusions:The up-regulation of miR-122 may play an important role in the progress of renal cancer through activatingPI3K/Akt signal pathway and could be a potential molecular target for anti-cancer therapeutics.     

IWR-1对人肝癌细胞株Hep3B的增殖及Wnt/β-catenin信号通路的抑制作用

目的 探讨IWR-1对人肝癌细胞株Hep3B细胞增殖的影响及可能的机制。方法 用不同浓度IWR-1（2、4、8、16μmol/L）处理Hep3B细胞,CCK-8法检测细胞生长抑制率;流式细胞仪检测细胞周期变化及细胞凋亡率;Western blot法检测细胞中蛋白表达的变化,实时定量RT-PCR检测β-catenin和c-myc mRNA表达的变化。结果 IWR-1对人肝癌Hep3B细胞的生长抑制作用呈现剂量和时间依赖性（P<0.01）。流式细胞术结果显示,Hep3B细胞的细胞周期呈现明显的G0/G1期阻滞,且细胞凋亡率明显升高（P<0.01）,呈现剂量依赖性。IWR-1可引起β-catenin和c-myc mRNA表达下降,β-catenin、c-myc蛋白表达下降,而Axin 1和p-β-catenin蛋白表达上升。结论 IWR-1可以抑制人肝癌细胞株Hep3B的增殖,其机制可能是通过抑制Wnt/β-catenin通路来实现。     

Primary Neuroendocrine Carcinoma of the Breast with Clinical Features of Inflammatory Breast Carcinoma: A Case Report and Literature Review

Primary neuroendocrine carcinoma of the breast (NECB) is a very rare type of invasive breast carcinoma. Most NECBs appear on breast imaging as solid masses of varied shapes and margins, and have worse clinical outcomes than does invasive ductal carcinoma, not otherwise specified. However, there have been no reports to date regarding NECB with features of inflammatory breast carcinoma. Here, we describe the clinical, radiol-ogic, and pathologic findings of the first reported case of primary NECB presenting as inflammatory breast carcinoma. The patient complained of diffuse right breast enlargement and erythema. Mammography identified severe breast edema and axillary lymphadenopathy. Ultrasound detected an irregular, angular, hypoechoic mass with dermal lymphatic dilatation. On magnetic resonance imaging, the mass had rim enhancement and the entire right breast showed heterogeneous enhancement with malignant kinetic features. Pathology identified the mass as a primary NECB with positive for synaptophysin, CD56, estrogen and progesterone receptors.     

Central Nervous System Metastasis in Patients With Urothelial Carcinoma: Institutional Experience and a Comprehensive Review of the Literature

IntroductionCentral nervous system (CNS) metastasis in patients with urothelial carcinoma (UC) is uncommon and poorly understood. We aimed to explore the clinical behavior and outcomes of this unique patient population.Materials and MethodsWe performed a retrospective analysis of patients with UC and CNS metastasis, treated in our institution (2006-2018), along with an exploratory patient-point meta-analysis of a similar patient population derived from a comprehensive literature review. Data regarding diagnosis, management, and outcomes were extracted. Overall survival, time to CNS metastasis (TTCM), and residual survival (RS) from CNS involvement to death were calculated (Kaplan–Meier method). Cox regression was used for testing key clinicopathologic associations.ResultsWe identified 20 “institutional” and 154 “literature” patients with adequate data granularity for analysis. Median TTCM was 17.7 (institutional cohort) and 10 (literature cohort) months. Most patients who developed CNS metastases had previous non-CNS metastasis (15/20 [75%] and 103/154 [67%], respectively). CNS lesions without previous history of metastasis were identified in 5/20 (25%) and 33/154 (21%) cases and those patients had a shorter TTCM. CNS lesions in the absence of known UC history were also documented in 18/154 (12%) literature cases. Multifocal CNS disease was associated with shorter RS in both cohorts in univariate, but not multivariate, analysis.ConclusionWe observed a variability in disease presentation and course, with a subset of patients showing an early predilection for CNS insult, potentially reflecting a diverse underlying biology. Genomic profiling studies, elucidating the molecular landscape, and driving future treatments should be considered in this setting.     

Impact of a Clinical Pathway on Hospital Costs,Length of Stay and Early Outcomes after Hepatectomy for Hepatocellular Carcinoma

Background: A clinical pathway (CP) can standardize and improve perioperative care for a number of interventions. In hepatic surgery, however, pertinent evidence is very limited. This study was conducted to implement a CP for hepatocellular carcinoma (HCC) patients undergoing hepatectomy, and to  evaluate its effects on hospital costs, length of hospital stay (LOHS) and early clinical outcomes. Materials and Methods: Medical records for HCC patients undergoing hepatectomy were retrospectively reviewed before implementation of a CP(the non-CP group) from March 2012 to August 2012. This information was compared with the data collected prospectively from patients after implementation of the CP (the CP group) between September 2012 and April 2013. Hospital costs, LOHS and early clinical outcomes were evaluated and compared between groups. Results: There were no significant differences in terms of patient clinical characteristics between the two groups. For clinical outcome measures, no significant differences were found in postoperative complications, mortality andreadmission rate. The hospital costs were significantly reduced from 24,844 RMB in the non-CP group to 19,761 RMB in the CP group (p<0.01). In addition, patients of the CP group also had shorter LOHS compared with the non-CP group (8.3 versus 12.3 days, p<0.001). Conclusions: The CP proved to be an effective approach to minimize hospital costs and LOHS with hepatectomy for HCC without compromising patient care.     

乳腺腺样囊性癌3例临床病理分析并文献复习

目的：探讨乳腺腺样囊性癌的病理形态学特点及ER，PR,p53，C-erb-B2的表达与其预后。方法：观查和分析3例乳腺腺样囊性癌的病理形态学特征，免疫组化染色表达并进行文献复习。结果：镜检病变形态与涎腺的腺样囊性癌相似，组织学上分为筛孔型、管状-小梁型和实体型三种类型。3例免疫组化均显示ER（-），PR（-），C-erb-B2（-），除1例p53（＋）外，另2例p53（-）。结论：发于乳腺的腺样囊性癌较罕见，预后良好，需与乳腺的筛状型导管内癌和筛状癌、分泌型癌病变鉴别。     

乳腺腺样囊性癌3例临床病理分析并文献复习

目的:探讨乳腺腺样囊性癌的病理形态学特点及ER,PR,p53,C-erb-B2的表达与其预后.方法:观查和分析3例乳腺腺样囊性癌的病理形态学特征,免疫组化染色表达并进行文献复习.结果:镜检病变形态与涎腺的腺样囊性癌相似,组织学上分为筛孔型、管状-小梁型和实体型三种类型.3例免疫组化均显示ER(-),PR(-),C-erb-B2(-),除1例p53(+)外,另2例p53(-).结论:发于乳腺的腺样囊性癌较罕见,预后良好,需与乳腺的筛状型导管内癌和筛状癌、分泌型癌病变鉴别.     

基于SNP芯片研究PI3K/Akt/mTOR通路上自噬相关基因SNPs与胃癌的关联

目的： 探讨与胃癌发生相关的PI3K/Akt/mTOR通路上新的与自噬相关基因单核苷酸多态性位点（SNPs），为寻找有价值的胃癌发生相关的分子标志物提供新的依据。方法： 采用1：1配对病例-对照研究的方法。通过KEGG pathway网站和Gene Ontology、Ensemble数据库及HaploView、STRING、Cytoscape软件联合SNP芯片筛选目标SNPs，采用基质辅助激光解吸电离飞行时间质谱（MALDI-TOF-MS）对筛检出来的SNPs位点在来自福建省仙游县的622例胃癌患者和622例健康人群基因组中进行验证。结果： SNP芯片及生物信息学分析筛选出IRS1 rs10205233、PIK3CD rs3934934、PIK3R1 rs706711、PIK3R1 rs706714和AKT1 rs35285446为候选位点。扩大样本验证发现IRS1 rs10205233的多态性变异（C > T）显著降低了胃癌的发病风险[共显性模型、显性模型的OR（95% CI）分别为0.761（0.595，0.975）、0.764（0.601，0.973）]。进一步分层分析，该位点显性模型、隐形模型、共显性模型以及等位基因在贲门癌和非贲门癌人群中均未见统计学差异（P > 0.05）。并未见其他位点与患胃癌风险的关联有统计学意义。对PIK3R1基因2个位点（rs706711、rs706714）的单体型分析也未见统计学差异。结论： IRS1 rs10205233位点与福建省胃癌高发区仙游县的胃癌发生存在关联，T等位基因可能是胃癌发生的一个遗传保护因素。     

基于SNP芯片研究PI3K/Akt/mTOR通路上自噬相关基因SNPs与胃癌的关联

目的： 探讨与胃癌发生相关的PI3K/Akt/mTOR通路上新的与自噬相关基因单核苷酸多态性位点（SNPs）,为寻找有价值的胃癌发生相关的分子标志物提供新的依据。方法： 采用1：1配对病例-对照研究的方法。通过KEGG pathway网站和Gene Ontology、Ensemble数据库及HaploView、STRING、Cytoscape软件联合SNP芯片筛选目标SNPs,采用基质辅助激光解吸电离飞行时间质谱（MALDI-TOF-MS）对筛检出来的SNPs位点在来自福建省仙游县的622例胃癌患者和622例健康人群基因组中进行验证。结果： SNP芯片及生物信息学分析筛选出IRS1 rs10205233、PIK3CD rs3934934、PIK3R1 rs706711、PIK3R1 rs706714和AKT1 rs35285446为候选位点。扩大样本验证发现IRS1 rs10205233的多态性变异（C > T）显著降低了胃癌的发病风险[共显性模型、显性模型的OR（95% CI）分别为0.761（0.595,0.975）、0.764（0.601,0.973）]。进一步分层分析,该位点显性模型、隐形模型、共显性模型以及等位基因在贲门癌和非贲门癌人群中均未见统计学差异（P > 0.05）。并未见其他位点与患胃癌风险的关联有统计学意义。对PIK3R1基因2个位点（rs706711、rs706714）的单体型分析也未见统计学差异。结论： IRS1 rs10205233位点与福建省胃癌高发区仙游县的胃癌发生存在关联,T等位基因可能是胃癌发生的一个遗传保护因素。